Digestion of consumed foodstuffs begins in the oral cavity where food is mechanically broken down by mastication, lubricated with saliva, and enzymatically processed by amylase present in the saliva. Digestion continues in the stomach where food is liquefied by gastric juices and enzymes secreted by the cells lining the stomach to produce chyme. Chyme enters the small intestine via the pyloric sphincter for further processing by bile salts produced by the liver and pancreatic digestive enzymes. Components not absorbed by or transported into the small intestine are subject to subsequent processing in the large intestine.
The rate at which chyme travels to the small intestine (gastric emptying rate) is the product of numerous physiological factors including, hormones, chemical signals in the ingesta, as well as signals from the nervous system.
A number of the population are affected by disorders that affect the emptying rate. For example, when the rate is accelerated, undigested food is prematurely dumped from the stomach to the small intestine. Conversely, when the rate is decelerated, the movement of ingested food from the stomach to the small intestine is delayed, giving rise to the condition termed “delayed emptying” otherwise known as gastroparesis.
Disorders involving gastric emptying rate are typically diagnosed by monitoring the rate at which a meal empties the stomach and enters the small intestine. In these tests, typically, an edible food is used to transport a marker into the gut of an animal and gastric emptying monitored by the marker.
Currently, the routine (gold standard) method for quantifying gastric emptying in humans is quantitative gastric scintigraphy. Scintigraphy involves the ingestion of a meal including at least one edible food, a component of which has been radiolabeled, and the subsequent measurement of gamma emission by a scintillation camera (positioned over the stomach) as the labeled food is emptied from the stomach.
The most common type of meal used in scintigraphy measurement of gastric emptying is a meal typically made by cooking 0.5 mCi 99mTc sulphur colloid with two raw eggs or 120 grams of a liquid egg substitute such as the product sold by ConAgra under the trademark Egg Beater®. In typical use, the patient fasts the night before the test. At the time of the test the patient consumes the cooked radiolabeled egg component with two slices of bread, 30 grams of jam and 120 ml of water. Scintigraphic scanning with anterior and posterior cameras is performed immediately after the test meal is consumed and scans are obtained every 15 minutes for two hours and every 30 minutes for up to six hours. Scintigraphy measurements of gastric emptying are direct, since the camera directly measures the meal exiting the stomach.
Scintigraphic results may be reported as “Percent Meal Emptied” or inversely, “Percent Meal Retained.” Typically, the % meal retained is calculated and reported at the 1, 2, 3, and 4 hour time point based on the amount of gamma radiation appearing at each respective time point. With time, more and more of the meal is emptied and hence there is less and less gamma radiation to be observed from the stomach. An evolving scintigraphic metric in the GI community defines slow gastric emptying as >10% of a meal remaining at the 4-hour time point when utilizing ˜225 kcal meal that has been demonstrated to empty in about 4 hours in healthy individuals. The greater the percent retained, the slower the gastric emptying rate. Two additional parameters are clinically useful in scintigraphic scanning. The first, tLAG, is the time required for the first 10% of the food to empty from the stomach. The second, t1/2, is the time required for half of the contents to be emptied from the stomach. Percent gastric retention of the radiolabel is calculated at each time point to generate a scintigraphic gastric retention curve. The curve is mathematically modeled with a power exponential model and the diagnostic result tLAG and t1/2 can be calculated from the curve.
Several disadvantages are associated with the traditional scintigraphy method. First, patients must be subjected to radioisotopes. This is particularly problematic for women of childbearing age or children. Further, the procedure must be carried out at specialized nuclear medicine facilities. Finally, the preparation for the procedure is cumbersome and potentially can introduce error to the test procedure. Prior to the procedure, personnel must prepare the labeled meal. Because cooking parameters or food quality, consistency and meal matrix may vary from hospital to hospital, standardization is lacking. For example, the caloric value, the matrix of meal and amount of scintigraphic scanning time vary from testing center to testing center. As with any medical test, standardization is of significant importance in gastric emptying test procedures.
Recently, a method for measuring gastric emptying has been described that utilizes an edible food labeled with non-radioactive markers. As the non-radioactive labeled edible food is digested, a labeled component is produced which can be detected in the patient's breath. This method is described in detail in U.S. Pat. No. 5,707,602, the teachings of which are hereby incorporated by reference. This patent describes the use of a nutritional supplement, Spirulina platensis, a blue green algae, grown in a highly enriched 13CO2 environment. The 13Carbon incorporated into the algal biomass acts as a non-radioactive marker. A small amount of the labeled algae is baked into a roll or breakfast bar and consumed by a patient with juice or water. The meal is triturated by the stomach to a particle size of approximately 1-2 mm and then passes from the stomach through the pylorous into the intestine. In the intestine, the labeled products of 13C-Spirulina platensis digestion are absorbed and metabolized giving rise to labeled carbon dioxide expired in the breath. The rate of 13CO2 appearance in the patient's breath (13CO2 excretion rate) is correlated to the rate of gastric emptying.
In contrast to scintigraphy, measurement of gastric emptying, in accordance with the marker described above, is indirect. Therefore, it is desirable to mathematically correlate the 13CO2 excretion curve to the scintigraphic gastric retention curve so that the emptying time of the stomach can be calculated from the 13CO2 curve. For example, one can use a general linear model to develop the relationship between diagnostic parameters obtained from scintigraphic measurements and the corresponding data obtained from the patient's 13CO2 excretion rate when both the radioactive scintigraphic label and 13C-label are administered simultaneously in the same meal.
To accurately correlate the 13CO2 excretion curve and the scintigraphic decay curve (which allows one to generate a predictive mathematical model from which the gastric emptying rate may be calculated using only 13CO2 excretion data), it is desirable to standardize the edible food and/or meal matrix delivering the marker to reduce the number of interfering variables. For example, if the new marker or drug (the surrogate marker) is incorporated into an edible food and/or meal (surrogate meal) that is different than the edible food and/or meal in which the well accepted marker or drug (predicate) is incorporated (predicate meal) the correlation process may be more difficult and or have poor predictive value. Thus, it is desirable for the predicate and surrogate meals to be as similar in composition, texture and nutritional content to each other as possible.
Similarly, such standardization allows for the validation of novel diagnostic or medical tests against well known, accepted tests ensuring accuracy and acceptance within the medical community. This may be particularly important where the new test detects, assesses, or measures physiological characteristics in a different manner, for example, indirectly versus directly.
In addition to standardization between novel and traditional medical tests, it is desirable that each individual method be standardized. It is desirable and often essential, that a medical test be performed identically each time it is conducted.
Thus, it is an object of the present invention to ensure reliability, reproducibility, accuracy and standardization when delivering a meal combined with a diagnostic marker or therapeutic drug into or beyond the stomach. It is further an object to provide a reliable method of validating the performance of the novel (surrogate) marker and measuring the absorption and/or activity of the drug or marker.